RARE DISEASE
Congenital nephrotic syndrome, Finnish type
Congenital nephrotic syndrome, Finnish type
Congenital nephrotic syndrome, Finnish type
Synonyms: Finnish congenital nephrosis
Synonyms: Finnish congenital nephrosis
Synonyms: Finnish congenital nephrosis
Drug discovery
129
papers
On emerging therapies
Overview
Congenital Nephrotic Syndrome, Finnish Type (CNF) is an autosomal recessive disorder caused by NPHS1 mutations disrupting nephrin, a critical podocyte protein. It manifests prenatally or within 3 months of life with severe proteinuria, hypoalbuminemia, edema, and complications like infections/thrombosis. Progression to end-stage kidney disease (ESKD) typically occurs by age 2–3 years. Diagnosis hinges on genetic testing, as immunosuppressants are ineffective. Management focuses on supportive care and renal transplantation [1][2][6][11].
Burden
High morbidity: Early ESKD, growth failure, thromboembolic events, and life-threatening infections [1][6][12].
Economic strain: Prolonged hospitalizations, albumin replacement, and dialysis/transplant costs [3][6][17].
Mortality: Historically fatal in infancy; modern strategies improve survival but require lifelong renal replacement therapy [1][16].
Therapies
Supportive care: Albumin infusions, RAS inhibitors (e.g., ACEi/ARBs), NSAIDs (indomethacin), anticoagulation, and thyroid supplementation [1][3][17].
Nephrectomy: Reduces proteinuria in refractory cases; bilateral nephrectomy precedes dialysis/transplant [9][17].
Transplantation: Definitive treatment with >90% 5-year graft survival; recurrence risk in Fin-major homozygotes [1][11][17].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
129 drug discovery papers about Congenital nephrotic syndrome, Finnish type, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
129 drug discovery papers about Congenital nephrotic syndrome, Finnish type, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-16 | Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome.
Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.
2024-10-01 | Establishment of a High-Throughput Screening System for Membrane Expression of Mutant Nephrin
Background: Congenital Nephrotic syndrome of the Finnish type (CNF) is caused by a mutation in the NPHS1 gene that hinders the cell surface expression of nephrin and disrupts slit membrane formation. In this study, we constructed a novel evaluation system to search for compounds promoting the expression of nephrin on the cell membrane. Methods: To detect the membrane-expressed nephrin, we used the HiBiT nanoluciferase system by tagging Nephrin wild-type (wt) and mutants (mt) with HiBiT. For high throughput screening (HTS), we generated stable expression cell lines of HiBiT- wt and mutant nephrin (HiBiT-Neph) using the Flp-InTM System. Phosphorylated-Nephrin, which indicates the ability to be translocated to the surface, was also assessed by immunoblotting. Results: In contrast to wt HiBiT-Neph, most mutants did not produce luminescence and were not phosphorylated. Furthermore, among the mutants, we confirmed that the reduction of HiBiT activity in the S366R and E725D stable mutant cells met the HTS criteria. Using E725D stable cells, we screened several chemical chaperones and a natural products compound library. Chemical chaperone β-alanine, a CFTR corrector (Corr-4a), and 78 compounds from the library increased the HiBiT-Neph E725D. Cytotoxicity assays and further validation by immunoblotting of phosphorylated nephrin trimmed the candidate compounds to ten. Focusing on these compounds, we revealed their effects on post-translational modifications and degradation rates of Nephrin to promote the expression of nephrin mutants on the membrane. Conclusion: The HTS evaluation system identified compounds that increased mutant nephrin phosphorylation and cell surface expression and showed that this evaluation system is useful as a drug discovery platform for CNF. Moreover, the identified compounds help to elucidate the mechanisms of mutant nephrin cell regulation.
2024-08-01 | Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis.
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
2024-07-12 | Effectiveness of Supramaximal Angiotensin-converting Enzyme Inhibition in Controlling Proteinuria in Congenital Nephrotic Syndrome with Cytomegalovirus Infection and an NPHS1 Mutation.
Congenital nephrotic syndrome (NS) is characterized by early-onset heavy proteinuria. Most cases of congenital NS are associated with genetic mutations in the podocyte proteins. The causal relationship of perinatal infections with congenital NS has not yet been proven. Inadequate response to the treatment of such infections should prompt us to conduct genetic testing for congenital NS. The heavy proteinuria associated with congenital NS is usually difficult to control with conventional treatment. It often results in progressive kidney disease with a high risk of mortality in early life. Here, we describe an infant who developed congenital NS and was found to have a coexisting Cytomegalovirus infection and an underlying NPSH1 mutation. Proteinuria did not respond to a standard dose of enalapril. A supramaximal dose of enalapril was tried and was effective and safe in controlling the proteinuria. It was associated with improved growth, complete resolution of edema, normal serum albumin, and normal renal function beyond 2 years of age.
2024-04-30 | Early diagnosis and management of finish type congenital nephrotic syndrome in a 3-year-old child: A case report
This study describes a 3-year-old non Finnish girl who was diagnosed with Finnish-type nephrotic syndrome (FTNS), a rare kidney illness brought on by NPHS1 gene abnormalities. Even though she had low protein levels and severe swelling when she was three months old, her case of congenital nephrotic syndrome (CNS) was incorrectly identified as minimal change disease (MCD). The standard MCD treatments, cyclosporine and steroids, did not affect her. A genetic test and a kidney sample confirmed the diagnosis of FTNS, a condition that necessitates an early renal transplant for survival. She is awaiting a kidney transplant and was treated with drugs that save proteins to lessen her edema. The study emphasizes the significance of FTNS early and correct diagnosis as well as the requirement for alternate treatments for this difficult illness.
proteins
2021-01-14 | Home Albumin Infusion Therapy, Another Alternative Treatment in Patients With Congenital Nephrotic Syndrome of the Finnish Type
Background: Congenital nephrotic syndrome of the Finnish type (CNF) is a rare, severe glomerular disease caused by mutations in the NPHS1 gene, which codes for nephrin. It is characterised by massive proteinuria and severe edoema. Progression to end-stage kidney failure occurs during early childhood and the only curative treatment is kidney transplantation. Nowadays, patients need aggressive medical treatment, which includes daily albumin infusions (for months) until they get clinical stability to receive transplant. Objective: In our paediatric hospital, we implemented a multidisciplinary program for the home infusion of albumin with outpatient follow-up. The aim of the study was to assess the safety and efficacy of this program for the first four years of its implementation. Material and Methods: Retrospective observational study of CNF paediatric patients treated with home albumin infusion therapy from March 2014 to July 2018 at a tertiary care paediatric hospital. Information on albumin administration was obtained from the electronic prescription assistance program and details on clinical and care-related variables from the hospital's electronic information systems. Results: Four patients with CNF received albumin infusions for 18, 21, 22 months, and 3 years. The treatment was safe, and the complication rates were to be expected considering the severity of disease. Patients required a median of two hospital admissions a year (19 in total); 47% due to catheter-related complications, but there were just three catheter infections. Conclusions: In our experience, home albumin infusion therapy is safe and effective and helps to improve children health and quality of life.
2020-12-22 | osr1 maintains renal progenitors and regulates podocyte development by promoting wnt2ba through antagonism of hand2
ABSTRACT Knowledge about the genetic pathways that control renal cell lineage development is essential to better understand the basis of congenital malformations of the kidney and design regenerative medicine therapies. The embryonic zebrafish kidney, or pronephros, contains two nephrons that are conserved with humans. Recently, the transcription factors Osr1 and Hand2 were found to exert antagonistic influences to balance kidney specification (Perens et al., 2016). Here, we performed a forward genetic screen in zebrafish to identify nephrogenesis regulators, where whole genome sequencing of the novel oceanside ( ocn ) mutant revealed a nonsense mutation in osr1. ocn mutants evince severe pronephros defects including abrogation of podocytes and proximal tubule cells. Our studies reveal that osr1 is not needed to specify renal progenitors, but rather required to maintain their survival. Additionally, osr1 is requisite for expression of the canonical Wnt ligand wnt2ba , where wnt2ba is expressed in the intermediate mesoderm (IM) and later restricts to podocytes. Deficiency of wnt2ba reduced podocyte progenitors, where overexpression of wnt2ba was sufficient to rescue the podocyte lineage as well as osr1 loss of function. Finally, we demonstrate that reciprocal antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression in the IM. Together, our data show that Osr1 is essential for a sequence of temporal functions that mediate the survival and lineage decisions of IM progenitors, and subsequently the maintenance of podocytes and proximal tubule epithelium in the embryonic nephron.
2019-06-06 | A specific isoform of Pyd/ZO-1 mediates junctional remodeling and formation of slit diaphragms
The podocyte slit diaphragm (SD), responsible for blood filtration in vertebrates, is a major target of injury in chronic kidney disease. The damage includes severe morphological changes with destabilization of SDs and their replacement by junctional complexes between abnormally broadened foot processes. In Drosophila melanogaster, SDs are present in nephrocytes, which filter the fly's hemolymph. Here, we show that a specific isoform of Polychaetoid/ZO-1, Pyd-P, is essential for Drosophila SDs, since, in pyd mutants devoid of Pyd-P, SDs do not form and the SD component Dumbfounded accumulates at ectopic septate-like junctions between abnormally aggregated nephrocytes. Reintroduction of Pyd-P leads to junctional remodeling and their progressive normalization toward SDs. This transition requires the coiled-coil domain of Pyd-P and implies formation of nonclathrin vesicles containing SD components and their trafficking to the nephrocyte external membrane, where SDs assemble. Analyses in zebrafish suggest a conserved role for Tjp1a/ZO-1 in promoting junctional remodeling in podocytes.
2018-02-20 | Treatment and outcome of congenital nephrotic syndrome
Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9–52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.
2017-07-31 | Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.
antibodies
2026-04-30 | Depletion of renal cortical collecting duct-secreted PCSK9 in early proteinuria prevents sustained nephrotic syndrome-related hypercholesterolemia.
The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin before peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, whereas both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia.NEW & NOTEWORTHY The goal of this study was to investigate the biology of CCD-secreted PCSK9 and its role in MCD-associated hypercholesterolemia. PCSK9 expression was increased in the kidney, but reduced in the liver, suggesting that elevated circulating PCSK9 levels may originate from the kidney. Administration of anti-PCSK9 antibodies targeting circulating kidney-derived PCSK9 prevented the development of significant and sustained hypercholesterolemia in the PAN rat model of human MCD-associated nephrotic syndrome.
2020-09-03 | Congenital Nephrotic Syndrome With a Novel Presentation in Saudi Arabia
Congenital nephrotic syndrome (CNS) is a rare and serious entity of renal diseases diagnosed in infants younger than three months. The triad of this syndrome is proteinuria, hypoalbuminemia, and edema. Without renal transplantation, these patients rarely live beyond the age of three years. Infections and sepsis are the most common causes of this condition among children. The majority of patients progress to end-stage renal disease early in life, even with aggressive supportive therapy. In this study, we present a case of a 10-year-old Saudi boy who had been diagnosed with CNS since he was two months old and has improved without renal transplantation.
2020-06-10 | Distinct Functional Requirements for Podocalyxin in Immature and Mature Podocytes Reveal Mechanisms of Human Kidney Disease
Abstract Dominant and recessive mutations in podocalyxin ( PODXL ) are associated with human kidney disease. Interestingly, some PODXL mutations manifest as anuria while others are associated with proteinuric kidney disease. PODXL heterozygosity is associated with adult-onset kidney disease and podocalyxin shedding into the urine is a common biomarker of a variety nephrotic syndromes. It is unknown, however, how various lesions in PODXL contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes Podxl in developmentally mature podocytes ( Podxl ∆Pod ) and a second that is heterozygous for podocalyxin in all tissues ( Podxl +/− ). We used histologic and ultrastructural analyses, as well as clinical chemistry assays to evaluate kidney development and function in these strains. In contrast to null knockout mice ( Podxl −/− ), which die shortly after birth from anuria and hypertension, Podxl ∆Pod mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. Podxl +/− mice, in contrast, have a normal lifespan, and fail to develop kidney disease under normal conditions. Intriguingly, although wild-type C57Bl/6 mice are resistant to puromycin aminonucleoside (PA)-induced nephrosis (PAN), Podxl +/− mice are highly sensitive and PA induces severe proteinuria and collapsing FSGS. In summary, we find that the developmental timepoint at which podocalyxin is ablated (immature vs. mature podocytes) has a profound effect on the urinary phenotype due to its critical roles in both the formation and the maintenance of podocyte ultrastructure. In addition, Podxl ∆Pod and Podxl +/− mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.
2016-01-08 | Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.
Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
2014-03-28 | Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation
Renal transplantation (RTx) is the only curative treatment for most cases of congenital and infantile nephrotic syndrome (NS) caused by genetic defects in glomerular podocyte proteins. The outcome of RTx in these children is usually excellent, with no recurrence of nephrotic syndrome. A subgroup of patients with the Finnish type of congenital nephrosis (CNF), shows, however, a clear risk for post-RTx proteinuria. Most of these patients have a homozygous truncating mutation (Fin-major mutation) in the nephrin gene (NPHS1), leading to total absence of the major podocyte protein, nephrin. After RTx, these patients develop anti-nephrin antibodies resulting in nephrotic range proteinuria. Plasma exchange combined with cyclophosphamide and anti-CD20 antibodies has proved to be successful therapy for these episodes. NS recurrence has also occurred in a few patients with mutations in the podocin gene (NPHS2). No anti-podocin antibodies have been detectable, and the pathophysiology of the recurrence remains open. While most of these episodes have resolved, the optimal therapy remains to be determined.
gene therapies
2025-12-04 | Congenital and infantile nephrotic syndrome: genotype-phenotype associations.
Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3-12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population. Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998-2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant's pathogenicity. NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset. Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach IMPACT: Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants. The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease. This knowledge can transform the management of Congenital Nephrotic Syndrome in children's healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.
2024-07-10 | Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type.
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1tm1Rkl/J. We assessed the phenotypic spectrum of homozygous mice (Nphs1tm1Rkl/Nphs1tm1Rkl) compared to heterozygous controls (Nphs1tm1Rkl/Nphs1WT) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1tm1Rkl/Nphs1tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.
2024-03-14 | Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies.
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model (Nphs1tm1.1Pgarg/J and Nphs2-Cre+) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice (Nphs1fl/fl Nphs2-Cre+) exhibited 1) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm2 compared with 4.36 µm/µm2 in controls; 3) a high number of proximal tubular microcysts; 4) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1fl/fl Nphs2-Cre+ mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects.NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin (Nphs1) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome.
2013-06-13 | Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury
We previously showed that mitochondrial dysfunction (MtD) is involved in an aldosterone (Aldo)-induced podocyte injury. Here, the potential role of MtD in the initiation of podocyte damage was investigated. We detected the dynamic changes of urinary protein, urinary F 2 -isoprostane and renal malondialdehyde levels, kidney ultrastructure morphology, mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (ΔΨ m ), and nephrin and podocin expressions in Aldo-infused mice. Aldo infusion first induced renal oxidative stress, as evidenced by increased levels of urinary F 2 -isoprostane and renal malondialdehyde, and MtD, as demonstrated by reduced mtDNA, ΔΨ m , and ATP production. Later, at 5 days after Aldo infusion, proteinuria and podocyte injury began to appear. In cultured podocytes, Aldo or hydrogen peroxide (H 2 O 2 ) induced MtD after 2–8 h of treatment, whereas the podocyte damage, as shown by decreased nephrin and podocin expressions, occurred later after 12 h of treatment. Thus Aldo treatment both in vitro and in vivo indicated that MtD occurred before podocyte damage. Additionally, MtDNA depletion by ethidium bromide or mitochondrial transcription factor A (TFAM) RNAi induced MtD, further promoting podocyte damage. TFAM expression was found to be reduced in Aldo-infused mice and Aldo-treated podocytes. Adenoviral vector-mediated overexpression of TFAM prevented Aldo-induced MtD and protected against podocyte injury. Together, these findings support MtD as an early event in podocyte injury, and manipulation of TFAM may be a novel strategy for treatment of glomerular diseases such as podocytopathy.
2011-04-22 | A Missense LAMB2 Mutation Causes Congenital Nephrotic Syndrome by Impairing Laminin Secretion
Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-type mouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.
small molecules
2025-11-16 | Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome.
Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.
2024-10-01 | Establishment of a High-Throughput Screening System for Membrane Expression of Mutant Nephrin
Background: Congenital Nephrotic syndrome of the Finnish type (CNF) is caused by a mutation in the NPHS1 gene that hinders the cell surface expression of nephrin and disrupts slit membrane formation. In this study, we constructed a novel evaluation system to search for compounds promoting the expression of nephrin on the cell membrane. Methods: To detect the membrane-expressed nephrin, we used the HiBiT nanoluciferase system by tagging Nephrin wild-type (wt) and mutants (mt) with HiBiT. For high throughput screening (HTS), we generated stable expression cell lines of HiBiT- wt and mutant nephrin (HiBiT-Neph) using the Flp-InTM System. Phosphorylated-Nephrin, which indicates the ability to be translocated to the surface, was also assessed by immunoblotting. Results: In contrast to wt HiBiT-Neph, most mutants did not produce luminescence and were not phosphorylated. Furthermore, among the mutants, we confirmed that the reduction of HiBiT activity in the S366R and E725D stable mutant cells met the HTS criteria. Using E725D stable cells, we screened several chemical chaperones and a natural products compound library. Chemical chaperone β-alanine, a CFTR corrector (Corr-4a), and 78 compounds from the library increased the HiBiT-Neph E725D. Cytotoxicity assays and further validation by immunoblotting of phosphorylated nephrin trimmed the candidate compounds to ten. Focusing on these compounds, we revealed their effects on post-translational modifications and degradation rates of Nephrin to promote the expression of nephrin mutants on the membrane. Conclusion: The HTS evaluation system identified compounds that increased mutant nephrin phosphorylation and cell surface expression and showed that this evaluation system is useful as a drug discovery platform for CNF. Moreover, the identified compounds help to elucidate the mechanisms of mutant nephrin cell regulation.
2024-08-01 | Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis.
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
2024-07-12 | Effectiveness of Supramaximal Angiotensin-converting Enzyme Inhibition in Controlling Proteinuria in Congenital Nephrotic Syndrome with Cytomegalovirus Infection and an NPHS1 Mutation.
Congenital nephrotic syndrome (NS) is characterized by early-onset heavy proteinuria. Most cases of congenital NS are associated with genetic mutations in the podocyte proteins. The causal relationship of perinatal infections with congenital NS has not yet been proven. Inadequate response to the treatment of such infections should prompt us to conduct genetic testing for congenital NS. The heavy proteinuria associated with congenital NS is usually difficult to control with conventional treatment. It often results in progressive kidney disease with a high risk of mortality in early life. Here, we describe an infant who developed congenital NS and was found to have a coexisting Cytomegalovirus infection and an underlying NPSH1 mutation. Proteinuria did not respond to a standard dose of enalapril. A supramaximal dose of enalapril was tried and was effective and safe in controlling the proteinuria. It was associated with improved growth, complete resolution of edema, normal serum albumin, and normal renal function beyond 2 years of age.
2024-04-30 | Early diagnosis and management of finish type congenital nephrotic syndrome in a 3-year-old child: A case report
This study describes a 3-year-old non Finnish girl who was diagnosed with Finnish-type nephrotic syndrome (FTNS), a rare kidney illness brought on by NPHS1 gene abnormalities. Even though she had low protein levels and severe swelling when she was three months old, her case of congenital nephrotic syndrome (CNS) was incorrectly identified as minimal change disease (MCD). The standard MCD treatments, cyclosporine and steroids, did not affect her. A genetic test and a kidney sample confirmed the diagnosis of FTNS, a condition that necessitates an early renal transplant for survival. She is awaiting a kidney transplant and was treated with drugs that save proteins to lessen her edema. The study emphasizes the significance of FTNS early and correct diagnosis as well as the requirement for alternate treatments for this difficult illness.
proteins
2021-01-14 | Home Albumin Infusion Therapy, Another Alternative Treatment in Patients With Congenital Nephrotic Syndrome of the Finnish Type
Background: Congenital nephrotic syndrome of the Finnish type (CNF) is a rare, severe glomerular disease caused by mutations in the NPHS1 gene, which codes for nephrin. It is characterised by massive proteinuria and severe edoema. Progression to end-stage kidney failure occurs during early childhood and the only curative treatment is kidney transplantation. Nowadays, patients need aggressive medical treatment, which includes daily albumin infusions (for months) until they get clinical stability to receive transplant. Objective: In our paediatric hospital, we implemented a multidisciplinary program for the home infusion of albumin with outpatient follow-up. The aim of the study was to assess the safety and efficacy of this program for the first four years of its implementation. Material and Methods: Retrospective observational study of CNF paediatric patients treated with home albumin infusion therapy from March 2014 to July 2018 at a tertiary care paediatric hospital. Information on albumin administration was obtained from the electronic prescription assistance program and details on clinical and care-related variables from the hospital's electronic information systems. Results: Four patients with CNF received albumin infusions for 18, 21, 22 months, and 3 years. The treatment was safe, and the complication rates were to be expected considering the severity of disease. Patients required a median of two hospital admissions a year (19 in total); 47% due to catheter-related complications, but there were just three catheter infections. Conclusions: In our experience, home albumin infusion therapy is safe and effective and helps to improve children health and quality of life.
2020-12-22 | osr1 maintains renal progenitors and regulates podocyte development by promoting wnt2ba through antagonism of hand2
ABSTRACT Knowledge about the genetic pathways that control renal cell lineage development is essential to better understand the basis of congenital malformations of the kidney and design regenerative medicine therapies. The embryonic zebrafish kidney, or pronephros, contains two nephrons that are conserved with humans. Recently, the transcription factors Osr1 and Hand2 were found to exert antagonistic influences to balance kidney specification (Perens et al., 2016). Here, we performed a forward genetic screen in zebrafish to identify nephrogenesis regulators, where whole genome sequencing of the novel oceanside ( ocn ) mutant revealed a nonsense mutation in osr1. ocn mutants evince severe pronephros defects including abrogation of podocytes and proximal tubule cells. Our studies reveal that osr1 is not needed to specify renal progenitors, but rather required to maintain their survival. Additionally, osr1 is requisite for expression of the canonical Wnt ligand wnt2ba , where wnt2ba is expressed in the intermediate mesoderm (IM) and later restricts to podocytes. Deficiency of wnt2ba reduced podocyte progenitors, where overexpression of wnt2ba was sufficient to rescue the podocyte lineage as well as osr1 loss of function. Finally, we demonstrate that reciprocal antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression in the IM. Together, our data show that Osr1 is essential for a sequence of temporal functions that mediate the survival and lineage decisions of IM progenitors, and subsequently the maintenance of podocytes and proximal tubule epithelium in the embryonic nephron.
2019-06-06 | A specific isoform of Pyd/ZO-1 mediates junctional remodeling and formation of slit diaphragms
The podocyte slit diaphragm (SD), responsible for blood filtration in vertebrates, is a major target of injury in chronic kidney disease. The damage includes severe morphological changes with destabilization of SDs and their replacement by junctional complexes between abnormally broadened foot processes. In Drosophila melanogaster, SDs are present in nephrocytes, which filter the fly's hemolymph. Here, we show that a specific isoform of Polychaetoid/ZO-1, Pyd-P, is essential for Drosophila SDs, since, in pyd mutants devoid of Pyd-P, SDs do not form and the SD component Dumbfounded accumulates at ectopic septate-like junctions between abnormally aggregated nephrocytes. Reintroduction of Pyd-P leads to junctional remodeling and their progressive normalization toward SDs. This transition requires the coiled-coil domain of Pyd-P and implies formation of nonclathrin vesicles containing SD components and their trafficking to the nephrocyte external membrane, where SDs assemble. Analyses in zebrafish suggest a conserved role for Tjp1a/ZO-1 in promoting junctional remodeling in podocytes.
2018-02-20 | Treatment and outcome of congenital nephrotic syndrome
Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9–52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.
2017-07-31 | Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.
antibodies
2026-04-30 | Depletion of renal cortical collecting duct-secreted PCSK9 in early proteinuria prevents sustained nephrotic syndrome-related hypercholesterolemia.
The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin before peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, whereas both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia.NEW & NOTEWORTHY The goal of this study was to investigate the biology of CCD-secreted PCSK9 and its role in MCD-associated hypercholesterolemia. PCSK9 expression was increased in the kidney, but reduced in the liver, suggesting that elevated circulating PCSK9 levels may originate from the kidney. Administration of anti-PCSK9 antibodies targeting circulating kidney-derived PCSK9 prevented the development of significant and sustained hypercholesterolemia in the PAN rat model of human MCD-associated nephrotic syndrome.
2020-09-03 | Congenital Nephrotic Syndrome With a Novel Presentation in Saudi Arabia
Congenital nephrotic syndrome (CNS) is a rare and serious entity of renal diseases diagnosed in infants younger than three months. The triad of this syndrome is proteinuria, hypoalbuminemia, and edema. Without renal transplantation, these patients rarely live beyond the age of three years. Infections and sepsis are the most common causes of this condition among children. The majority of patients progress to end-stage renal disease early in life, even with aggressive supportive therapy. In this study, we present a case of a 10-year-old Saudi boy who had been diagnosed with CNS since he was two months old and has improved without renal transplantation.
2020-06-10 | Distinct Functional Requirements for Podocalyxin in Immature and Mature Podocytes Reveal Mechanisms of Human Kidney Disease
Abstract Dominant and recessive mutations in podocalyxin ( PODXL ) are associated with human kidney disease. Interestingly, some PODXL mutations manifest as anuria while others are associated with proteinuric kidney disease. PODXL heterozygosity is associated with adult-onset kidney disease and podocalyxin shedding into the urine is a common biomarker of a variety nephrotic syndromes. It is unknown, however, how various lesions in PODXL contribute to these disparate disease pathologies. Here we generated two mouse stains: one that deletes Podxl in developmentally mature podocytes ( Podxl ∆Pod ) and a second that is heterozygous for podocalyxin in all tissues ( Podxl +/− ). We used histologic and ultrastructural analyses, as well as clinical chemistry assays to evaluate kidney development and function in these strains. In contrast to null knockout mice ( Podxl −/− ), which die shortly after birth from anuria and hypertension, Podxl ∆Pod mice develop an acute congenital nephrotic syndrome characterized by focal segmental glomerulosclerosis (FSGS) and proteinuria. Podxl +/− mice, in contrast, have a normal lifespan, and fail to develop kidney disease under normal conditions. Intriguingly, although wild-type C57Bl/6 mice are resistant to puromycin aminonucleoside (PA)-induced nephrosis (PAN), Podxl +/− mice are highly sensitive and PA induces severe proteinuria and collapsing FSGS. In summary, we find that the developmental timepoint at which podocalyxin is ablated (immature vs. mature podocytes) has a profound effect on the urinary phenotype due to its critical roles in both the formation and the maintenance of podocyte ultrastructure. In addition, Podxl ∆Pod and Podxl +/− mice offer powerful new mouse models to evaluate early biomarkers of proteinuric kidney disease and to test novel therapeutics.
2016-01-08 | Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.
Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
2014-03-28 | Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation
Renal transplantation (RTx) is the only curative treatment for most cases of congenital and infantile nephrotic syndrome (NS) caused by genetic defects in glomerular podocyte proteins. The outcome of RTx in these children is usually excellent, with no recurrence of nephrotic syndrome. A subgroup of patients with the Finnish type of congenital nephrosis (CNF), shows, however, a clear risk for post-RTx proteinuria. Most of these patients have a homozygous truncating mutation (Fin-major mutation) in the nephrin gene (NPHS1), leading to total absence of the major podocyte protein, nephrin. After RTx, these patients develop anti-nephrin antibodies resulting in nephrotic range proteinuria. Plasma exchange combined with cyclophosphamide and anti-CD20 antibodies has proved to be successful therapy for these episodes. NS recurrence has also occurred in a few patients with mutations in the podocin gene (NPHS2). No anti-podocin antibodies have been detectable, and the pathophysiology of the recurrence remains open. While most of these episodes have resolved, the optimal therapy remains to be determined.
gene therapies
2025-12-04 | Congenital and infantile nephrotic syndrome: genotype-phenotype associations.
Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3-12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population. Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998-2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant's pathogenicity. NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset. Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach IMPACT: Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants. The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease. This knowledge can transform the management of Congenital Nephrotic Syndrome in children's healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.
2024-07-10 | Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type.
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1tm1Rkl/J. We assessed the phenotypic spectrum of homozygous mice (Nphs1tm1Rkl/Nphs1tm1Rkl) compared to heterozygous controls (Nphs1tm1Rkl/Nphs1WT) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1tm1Rkl/Nphs1tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.
2024-03-14 | Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies.
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model (Nphs1tm1.1Pgarg/J and Nphs2-Cre+) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice (Nphs1fl/fl Nphs2-Cre+) exhibited 1) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm2 compared with 4.36 µm/µm2 in controls; 3) a high number of proximal tubular microcysts; 4) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1fl/fl Nphs2-Cre+ mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects.NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin (Nphs1) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome.
2013-06-13 | Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury
We previously showed that mitochondrial dysfunction (MtD) is involved in an aldosterone (Aldo)-induced podocyte injury. Here, the potential role of MtD in the initiation of podocyte damage was investigated. We detected the dynamic changes of urinary protein, urinary F 2 -isoprostane and renal malondialdehyde levels, kidney ultrastructure morphology, mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (ΔΨ m ), and nephrin and podocin expressions in Aldo-infused mice. Aldo infusion first induced renal oxidative stress, as evidenced by increased levels of urinary F 2 -isoprostane and renal malondialdehyde, and MtD, as demonstrated by reduced mtDNA, ΔΨ m , and ATP production. Later, at 5 days after Aldo infusion, proteinuria and podocyte injury began to appear. In cultured podocytes, Aldo or hydrogen peroxide (H 2 O 2 ) induced MtD after 2–8 h of treatment, whereas the podocyte damage, as shown by decreased nephrin and podocin expressions, occurred later after 12 h of treatment. Thus Aldo treatment both in vitro and in vivo indicated that MtD occurred before podocyte damage. Additionally, MtDNA depletion by ethidium bromide or mitochondrial transcription factor A (TFAM) RNAi induced MtD, further promoting podocyte damage. TFAM expression was found to be reduced in Aldo-infused mice and Aldo-treated podocytes. Adenoviral vector-mediated overexpression of TFAM prevented Aldo-induced MtD and protected against podocyte injury. Together, these findings support MtD as an early event in podocyte injury, and manipulation of TFAM may be a novel strategy for treatment of glomerular diseases such as podocytopathy.
2011-04-22 | A Missense LAMB2 Mutation Causes Congenital Nephrotic Syndrome by Impairing Laminin Secretion
Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-type mouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.
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